Colchicine, a major alkaloid of Colchium autumnale, is used for treatment of some diseases, such as acute gout, familial Mediterranean fever (FMF), and chronic myelocytic leukemia (Brossi). Colchicine has also been reported as an inhibitor of HIV replication (Baum).
Colchicine exerts its anti-inflammatory and anti-proliferative effects through binding to the microtubular protein tubulin preventing tubulin polymerization. Inhibition of tubulin polymerization can lead either to inhibition of leukocyte migration and phagocytosis limiting inflammation associated with acute gout or to inhibition of cellular mitosis decreasing cellular proliferation associated with cancer (Brossi, Shearn).
Treatment of disease with colchicine suffers from two drawbacks. Colchicine doses required to effect its therapeutic actions are usually at toxic or nearly toxic doses. Secondly, cells can become resistant to colchicine by overproducing the p170 glycoprotein drug-efflux pump (Goz).
Numerous chemical modification studies have been performed to enhance colchicine binding to tubulin, while minimizing cellular toxicity (Brossi). For example, selective demethylation at each of four methoxy groups of colchicine (C(1), C(2), C(3), or C(10)) can be performed. Of these four colchine derivatives only 3-demethylcolchicine, a colchicine derivative lacking a methoxy group at C(3), shows good antitubulin binding activity. The structure of colchicine is illustrated in FIG. 1.
Modification of the amide group in colchicine has also been investigated. For example, the ethyl carbamate of deacetylcolchicine is a potent inhibitor of tubulin polymerization activity (Muzaffar). The tropolonic ring of colchicine (ring C in FIG. 1) has been modified replacing the C(10) methoxy group with amines and amino acid esters resulting in biologically active compounds (Leiter).